A Phase I/II First in Human Study of the Menin-MLL(KMT2A) Inhibitor KO-539 in Patients With R elapsed or Refractory Acute Myeloid Leukemia
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Study Summary
To evaluate KO-539 in patients with acute myeloid leukemia and acute lymphoblastic leukemia To determine the maximum tolerated dose (MTD) of KO-539, a menin-MLL(KMT2A) inhibitor, in patients with refractory or relapsed AML who have failed or are ineligible for any approved standard of care therapies, including HSCT To determine the safety and tolerability of escalating doses using a modified toxicity probability interval (mTPI) adaptive design when administered to patients with relapsed and/or refractory AML To determine the recommended Phase 2 dose or maximum tolerated dose of KO-539 in patients with relapsed or refractory AML. To assess safety, tolerability, pharmacokinetics, and anti-leukemic activity To assess safety and tolerability, characterize the pharmacokinetics (PK), and determine a recommended Phase 2 dose The Phase 2A dose expansion portion will assess anti-leukemic activity, PK, safety and tolerability in select genetic subtypes of AML. Preclinically, the drug is shown to be highly protein bound (>99%) across animal species. Using physiologically-based PK (PBPK) modeling, the estimated human efficacious dose was estimated to be 600 mg po qd. The objectives of the Phase (Ph) 1 dose escalation are to assess safety and tolerability, characterize the pharmacokinetics (PK), determine a recommended Ph2 dose (RP2D), and investigate early signs of anti-leukemic activity. The Ph1 expansion cohorts will assess anti-leukemic activity, PK, safety and tolerability in AML pts with NPM1 mutation or KMT2A rearrangement at doses that have already met the safety threshold to help determine a minimally safe and biologically effective dose. Once a RP2D has been determined, Ph2 expansion cohorts including AML pts with NPM1 mutation or KMT2A rearrangements will be conducted to assess safety, tolerability and efficacy at the RP2D. Part 1a: Dose-Escalation To determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of KO-539 in patients with relapsed or refractory acute myeloid leukemia (AML). Part 1b: Dose-Validation/ Cohort Expansion The dose-validation/expansion part of the study (part 1b) will determine the safety, tolerability, and minimal biologically effective dose of ziftomenib (KO-539) in dosing cohorts which have demonstrated early biological activity and have been determined to be safe in the dose-escalation part. To present preliminary KOMET-001 (NCT04067336) data, an ongoing Phase (P) 1/2 study of ziftomenib (KO-539), an inhibitor of KMT2A-menin interaction, in adult pts with relapsed/refractory (R/R) AML. Ziftomenib is dosed orally, once daily, in 28-day cycles. To determine the safety, tolerability, and anti-leukemia activity of ziftomenib in patients with NPM1-m AML. To establish the safety andrecommended phase 2 dose (RP2D) for ziftomenib monotherapy in NPM1m and KMT2Ar R/R AML To establish the safety, tolerability, andrecommended phase 2 dose (RP2D) for ziftomenib monotherapy in NPM1-m and KMT2A-r R/R AML To assess evidence of clinical activity, safety and tolerability of ziftomenib, the only investigational therapy to receive Breakthrough Therapy Designation (BTD) from the FDA for treatment of R/R NPM1-mutant AML
- Patients with refractory or relapsed AML defined as the reappearance of ≥ 5% blasts in the bone marrow and who have also failed or are ineligible for any approved standard of care therapies, including HSCT.
- Phase 1b:
- Patients with a documented lysine[K]-specific methyltransferase 2-rearrangement (KMT2A-r), or
- Patients with a documented nucleophosmin 1 mutation (NPM1-m)
- Phase 2:
- Patients with a documented nucleophosmin 1 mutation (NPM1-m)
- Sub-studies:
- Sub-studies 1 and 2: Patients with R/R AML with NPM1-m or other mutations associated with MEIS1 overexpression.
- Sub-study 3: Patients with R/R Acute Lymphoblastic Leukemia (ALL) with KMT2A-r.
- Sub-study 4: Patients with R/R AML with mutations associated with MEIS1 overexpression.
- ≥ 18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and a life expectancy of at least 2 months.
- Adequate liver and kidney function according to protocol requirements.
- Peripheral white blood cell (WBC) counts ≤ 30,000/μL. Patients may receive hydroxyurea to control and maintain white blood cell count prior to enrollment.
- Women of childbearing potential must be willing to use a highly effective method of contraception throughout the study and for at least 187 days after the last dose of study treatment.
- Males with female partners of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 97 days after the last dose of study treatment.
- Diagnosis of acute promyelocytic leukemia.
- Diagnosis of chronic myelogenous leukemia in blast crisis.
- Donor lymphocyte infusion < 30 days prior to study entry.
- Clinically active central nervous system (CNS) leukemia.
- Undergone HSCT and have not had adequate hematologic recovery.
- Receiving immunosuppressive therapy post HSCT within 2 weeks of Cycle 1 Day 1.
- Grade ≥ 2 active graft-versus-host disease (GVHD), moderate or severe limited chronic GVHD, or extensive chronic GVHD of any severity.
- Received chemotherapy immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational (i.e., used for non-approved indications(s) and in the context of a research investigation) < 14 days prior to the first dose of ziftomenib or within 5 drug half-lives prior to the first dose of study drug.
- Not recovered to < Grade 2 (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) from all acute toxicities or deemed back to a stable baseline.
- Treatment with concomitant drugs that are strong inhibitors or inducers of cytochrome P450-isozyme 3A4 (CYP3A4), as follows:
- Phase 1a, 1b, 2, and sub-studies 3 and 4: with the exception of antibiotics, antifungals, and antivirals that are used as standard of care or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient.
- Sub-studies 1 and 2: No exceptions will be allowed except for the use of moderate CYP3A4 antifungal prophylaxis such as fluconazole or isavuconazole which is at steady state on Cycle 1 Day 1 and will continue through the completion of PKs on Cycle 1 Day 15 (for sub-study 1) or Cycle 1 Day 18 (for sub-study 2).
- Detectable viral load for human immunodeficiency virus, hepatitis C, or hepatitis B surface antigen indicative of active infection. Patients with controlled disease will not be excluded from study enrollment.
- Pre-existing disorder predisposing the patient to a serious or life-threatening infection (e.g. cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenias not related to AML).
- Active uncontrolled acute or chronic systemic fungal, bacterial, viral, or other infection.
- Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, history of cerebrovascular accident including transient ischemic attack within the past 6 months, congestive heart failure (NYHA Class III or IV) related to primary cardiac disease, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the first dose of study treatment.
- Mean QTcF >480 ms on triplicate ECG.
- Major surgery within 4 weeks prior to the first dose of study treatment.
- Women who are pregnant or lactating. All female patients with reproductive potential must have a negative serum pregnancy test within 72 hours prior to starting treatment.
- For sub-studies 1 and 2: Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of ziftomenib until the end of Cycle 1.
- For sub-studies 1 and 2: Moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.
Clinical Study Information for Healthcare Providers
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